Pancreatic islet transplantation has not been adapted and applied to the treatment of large numbers of human diabetic patients because: (1) The long-term effects of islet transplants are not fully understood, and the overall safety of the procedure has not been established. (2) Experimental data suggests that high dose immunosuppressive drug treatments would be required to prevent the rejection of islet transplants, and it is generally held that the complications of diabetes are less serious than those which are known to accompany chronic immunosuppression. (3) The supply of human cadaveric pancreatic islets is limited. The aims of the proposed research are two-fold: (1) To define fully the metabolic and morphologic effects of pancreatic islet transplantation by means of long-term correlative studies of a broad range of subjects using animal models. (2) To develop methods for immunologic modification of islet donors, islets in tissue culture and/or islet recipients in non-toxic ways in order to circumvent graft rejection and allow both allogeneic and xenogeneic islet transplantation.